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This article reviews the current pathogenesis, molecular changes, diagnosis, and treatment of ocular melanomas. Ocular melanomas can involve the eyelid, conjunctiva, intraocular structures, and the orbit. The most common eye melanoma involves the uveal tract and is responsible for approximately 13% of melanoma deaths. Uveal melanomas account for 10% of all melanomas.
The reliability of clinical methods is often taken for granted. There is considerable evidence, however, that variability of clinical measurements, interpretations, and judgements are greater than commonly thought. Inconsistency of clinical methods has profound and widespread implications in clinical practice. The inferential capacity of measurements depends on accuracy and reproducibility. Appropriate medical decisions cannot be reached without accurate and reliable data. This review will examine the conceptual relationship of reliability, accuracy, and validity. The role of observer reliability in ophthalmic test measurements and interpretations will be addressed in the context of three case reports.
The ocular adnexal lymphomas represent the malignant end of the spectrum of lymphoproliferative lesions that occur in these locations. The Revised European and American Lymphoma (REAL) Classification and the new World Health Organization Classification of Tumors of Hemopoietic and Lymphoid Tissues are the most suitable for subdividing the ocular adnexal lymphomas, whereby the extranodal marginal zone B-cell lymphoma represents the most common lymphoma subtype. This review is based on five cases subtyped according to the above classifications-three "typical" lymphomas (an extranodal marginal zone B-cell lymphoma, a diffuse large cell B-cell lymphoma arising from an extranodal marginal zone B-cell lymphoma, and a follicular lymphoma) and two "atypical" lymphomas (a non-endemic Burkitt lymphoma in an immune competent elderly patient, and a primary Hodgkin lymphoma of the eyelid) of the ocular adnexa. Management of patients with ocular adnexal lymphomas includes a thorough systemic medical examination to establish the clinical stage of the disease. The majority of patients with ocular adnexal lymphoma have stage IE disease. Current recommended therapy in stage IE tumors is radiotherapy, while disseminated disease is treated with chemotherapy. Despite usually demonstrating an indolent course, extranodal marginal zone B-cell lymphomas are renowned for recurrence in extranodal sites, including other ocular adnexal sites. Long-term follow-up with 6-month examinations are therefore recommended. Major prognostic criteria for the ocular adnexal lymphomas include anatomic location of the tumor; stage of disease at first presentation; lymphoma subtype as determined using the REAL classification; immunohistochemical markers determining factors such as tumor growth rate; and the serum lactate dehydrogenase level.
Ocular surface squamous neoplasia presents as a spectrum from simple dysplasia to carcinoma in situ to invasive squamous cell carcinoma involving the conjunctiva as well as the cornea. It is a distinct clinical entity, although it has been known by a variety of different names throughout the literature. Most commonly it arises in the limbal region, occurring particularly in elderly males who have lived in geographic areas exposed to high levels of ultraviolet-B radiation. Symptoms range from none to severe pain and visual loss. The development of preoperative diagnostic techniques, such as impression cytology, are of value in clinical decision making and follow-up management. Simple excision with adequate margins is currently the best established form of treatment despite trials of other modalities. The course of this disease may be evanescent, but is more frequently slowly progressive and may require exenteration and occasionally may lead to death.
Two patients with intraepithelial sebaceous neoplasia of the conjunctiva and cornea without an underlying invasive carcinoma are described. This intraepithelial disease displays the same cytologic features found in the conjunctival epithelium of patients with an invasive sebaceous carcinoma. The natural history of this incipient carcinoma is unknown. Anecdotal evidence indicates that some lesions can remain in situ for prolonged periods without undergoing transformation to an invasive carcinoma. The diagnosis of intraepithelial sebaceous neoplasia of the ocular surface is established by excluding an occult invasive carcinoma with appropriate biopsies.
Conjunctival melanoma is an uncommon tumor that is likely to recur and carries an overall mortality rate of approximately 30%. The seemingly unpredictable and enigmatic character of this entity has initiated much debate over the past decades regarding the etiology, histogenesis, prognosis, and preferred management. This review outlines the historical perspective; incidence and demographics; etiologic factors; histogenesis; cytogenetic findings; clinical characteristics; histopathologic and ultrastructural features; differential diagnoses; classifications; management of primary, recurrent, and systemic disease; survival after conjunctival melanoma; and diverse factors of potential prognostic significance. Finally, a brief outlook on present and future research objectives is provided.
Forty-one cases of conjunctival primary acquired melanosis (PAM) were studied to determine the frequency of progression to malignant melanoma and to establish prognostic parameters for progression to melanoma. Two subdivisions were identified: lesions with cytologically atypical melanocytes (PAM with atypia, 28 lesions, 68.3 per cent) and those lacking cytologically atypical melanocytes (PAM without atypia, 13 lesions, 31.7 per cent). None of the lesions of PAM without atypia progressed to melanoma. Thirteen of the 28 lesions of PAM with atypia (46.4 per cent) progressed to melanoma. Progression to melanoma was more frequent in the lesions of PAM with atypia if basilar hyperplasia was not the dominant histologic pattern (90 per cent progression, P = 0.02) or if any epithelioid cells were present (75 per cent progression, P = 0.02). It was not possible to determine which lesions were atypical on the basis of clinical appearance. Lesions at risk for the development of melanoma should be totally extirpated.
One hundred thirty-one cases of conjunctival melanoma in which biopsies had been performed were studied to determine potential factors that might affect outcome in patients with these lesions. Two groups of lesions were identified: those associated with primary acquired melanosis (melanoma with PAM, 98 cases, 74.8 per cent) and those without primary acquired melanosis (melanoma without PAM, 33 cases, 25.2 per cent). The overall mortality rate in the 131 cases was 26 per cent (34 of 131); the mortality rate due to melanoma with PAM was 25.5 per cent (25 of 98), and that due to melanoma without PAM was 27.3 per cent (9 of 33). If PAM was associated with the lesion, the presence of atypical melanocytes within the epithelium (pagetoid invasion) was a sensitive indicator of subsequent metastasis. Tumor thickness may also be useful for predicting subsequent metastases. None of the histologic parameters studied proved useful for predicting outcome in patients who had melanomas without PAM. The presence or absence of nevi had no effect on prognosis.
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Twenty-three conjunctival papillomas and 28 conjunctival dysplasias were examined for human papillomavirus (HPV)-DNA sequences by in situ hybridization with nick-translated 35S-labeled HPV probes. Adjacent paraffin sections were hybridized with HPV type 2, 6, 16, and 18 probes at Tm - 17 degrees C. Fifteen tissues, all papillomas, displayed positive hybridization with the HPV-6 probe. Infection with HPV-6 (or the closely related HPV-11) appeared to be responsible for most of the conjunctival papillomas of children and young adults. The presence of genital tract HPV-6 in these lesions suggests that some of the infections were acquired during passage through an infected birth canal. The lack of hybridization in adult conjunctival dysplasias indicates either that HPVs are not associated with this condition or that the probes and the technique utilized were not adequate for demonstration of this association.
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The incidence of conjunctival squamous-cell carcinoma in Kampala, Uganda, was steady at around 6 per million per year from 1970 until 1988, but has increased six-fold since then to 35 per million per year in 1992. Among 48 patients with conjunctival tumours seen at the ophthalmology clinic of the New Mulago Hospital from 1990 to 1991, 75% were HIV seropositive, compared with a 19% seropositivity rate among 48 matched controls (relative risk 13.0, 95% CI 4.5-39.4, p < 0.0001). The recent epidemic of conjunctival tumours in Uganda (and in neighbouring countries) appears to be largely due to the epidemic of HIV infection. Other factors that may contribute to the high incidence of these tumours in equatorial Africa may be exposure to ultraviolet light and conjunctival papillomavirus infection.
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BACKGROUND: We have investigated the geographic distribution of squamous-cell carcinoma of the eye to assess whether solar ultraviolet light is a risk factor for this disease. METHODS: We used routinely collected population-based cancer incidence data and published measurements of ambient solar ultraviolet light in our analysis. FINDINGS: The incidence of squamous-cell carcinoma of the eye declined by 49% of each 10 degrees increase in latitude (p < 0.0001), falling from more than 12 cases per million per year in Uganda (latitude 0.3(0)) to less than O.2 per million per year in the UK (latitude > 50(0)). Solar ultraviolet radiation decreases with increasing latitude, and the incidence of squamous-cell carcinoma of the eye decreased by 29% per unit reduction in ultraviolet exposure (p < 0.0001). INTERPRETATION: Our results are compatible with the hypothesis that exposure to solar ultraviolet light is an important cause of squamous-cell carcinoma of the eye.
BACKGROUND: MALT (Mucosal Associated Lymphoid Tissue) lymphomas of the conjunctiva belong to the extranodal marginal zone B-cell lymphomas. This site, while standard, is uncommon. CASE-REPORT: A pink papular tumor developed on the lower eyelid of a 59-year-old woman. Sarcoidosis was diagnosed 9 years earlier associated with mediastinal lymphadenopathy and erythema nodosum not requiring treatment. Histological examination yielded a diagnosis of conjunctival MALT lymphoma. No visceral involvement was demonstrated. Radiotherapy (30 Gy) induced a complete response. A remote lesion developed on the patient's arm 18 months later. No other sites were found. Further radiotherapy (26 Gy) again induced complete remission. No new lesions were seen after 24 months of follow-up. DISCUSSION: This case is interesting because of the association of a MALT lymphoma and previous sarcoidosis, described in the literature as "sarcoidosis-lymphoma syndrome". Association of sarcoidosis with MALT lymphoma is infrequent. Treatment of conjunctival MALT lymphoma is standardized. Radiotherapy offers excellent efficacy and is well tolerated at this site. Regular and long-term follow-up is required. Local and distant relapse can occur.
OBJECTIVE: To evaluate the results on malignant melanomas of the eyelid and palpebral conjunctiva treated with iodine-125 (125I) brachytherapy with shielding of the eye. DESIGN: Noncomparative case series. PARTICIPANTS: Fourteen patients treated with 125I brachytherapy at an ocular oncology referral center from 1974 through 1996, all of whom had had previous debulking, incomplete resection, or recurrence after surgery. INTERVENTION: A stainless steel pericorneal ring eyeshield was attached to the extraocular muscles, over which a lid was fitted to protect the cornea without touching it. Iodine-125 seeds in polythene tubes were inserted into the eyelid and attached to the lid margin for a single plane implant. In five cases additional seeds were glued on to the shield as well for a volume implant. A median dose of 37 Gy (range, 17.3-67.6 Gy) was given over the course of 113 hours (range, 47-190 hours) to the outer surface of target volume. MAIN OUTCOME MEASURES: Local control is regarded as freedom from recurrence in those without measurable disease and complete clinical regression in those with measurable disease. Morbidity is assessed in terms of function and cosmesis. Survival is given from the time of the implant. RESULTS: There was local control in 13 patients maintained from 11 to 227 months (median, 39 months). There were two recurrences at 8 and 13 months in the first patient who received 17.3 Gy. Late complications consisted of mild eyelid telangiectasia, mild eyelid atrophy, and loss of eyelashes in most patients. Five patients, four of whom had upper eyelid tumors, experienced a dry eye, which was managed with tear supplements, and one of these patients developed a cataract. A corneal ulcer developed in one eye, which later perforated after treatment of a subsequent bulbar melanoma and was exenterated. Another eye was enucleated after treatment for a subsequent melanoma in the fornix. Cosmesis was acceptable to patient and doctor in the other 12 patients. Vision was maintained in seven patients, reduced in two, and not recorded in the remaining three patients. Three patients died of hematogenous metastases at 44, 62, and 79 months after implant, one of bronchial carcinoma at 46 months and one of an astrocytoma at 39 months. All patients were clear of local disease. The remainder survived for a median of 45 months (range, 18-227 months). CONCLUSIONS: Iodine-125 brachytherapy can be used as an alternative to wide excision or exenteration of these tumors. There was good local control, reasonable maintenance of vision, and good cosmesis.